The goal of this application is to determine the molecular mechanism underlying diabetic neuropathy in dorsal root ganglion (DRG) neurons. Our hypothesis is that neurons exposed to high glucose undergo apoptosis via activation of apoptosis signal-regulated kinase 1 (ASKI), which activates the c-Jun N-terminal kinase (JNK) pathway. Insulin-like growth factor I (IGF-I) is predicted to protect DRG from glucose-mediated apoptosis by blocking activation of a component of the JNK pathway. This application will analyze glucose-treated DRG by TUNEL analysis and western blotting to determine 1) apoptotic molecules induced by JNK activation, 2) the role of ASKI on JNK activation and apoptosis and 3) the effect of IGF-I on JNK pathway activation and apoptotic regulatory proteins. At the conclusion of these studies we will understand how the JNK pathway functions in a model of diabetic neuropathy and how IGF-I mediates neuroprotection. These findings will advance our understanding of neuronal injury and may suggest potential therapeutic interventions for treatment of diabetic neuropathy.